HER3-Mediated Resistance to Hsp90 Inhibition Detected in Breast Cancer Xenografts by Affibody-Based PET Imaging.

Abstract

<b>Purpose:</b> Recent studies have highlighted a role of HER3 in HER2-driven cancers (e.g., breast cancer), implicating the upregulation of the receptor in resistance to HER-targeted therapies and Hsp90 inhibitors (e.g., AUY922). Therefore, we have developed an affibody-based PET radioconjugate that quantitatively assesses HER3 changes induced by Hsp90 inhibition <i>in vivo</i><b>Experimental Design:</b> Z_HER3:8698 affibody molecules were conjugated via the C-terminus cysteine to DFO-maleimide for ⁸⁹Zr radiolabeling. The probe was characterized <i>in vitro</i> and <i>in vivo</i> in a panel of human breast cell lines and xenograft models with varying HER3 receptor levels. In addition, the radioconjugate was investigated as a tool to monitor the outcome of AUY922, an Hsp90 inhibitor, in an MCF-7 xenograft model.<b>Results:</b> We demonstrated that ⁸⁹Zr-DFO-Z_HER3:8698 can track changes in receptor expression in HER3-positive xenograft models and monitor the outcome of AUY922 treatment. Our <i>in vitro</i> findings showed that MCF-7 cells, which are phenotypically different from BT474, develop resistance to treatment with AUY922 through HER3/IGF-1Rβ-mediated signaling. Of note, the lack of response <i>in vitro</i> due to HER3 recovery was confirmed <i>in vivo</i> using ⁸⁹Zr-DFO-Z_HER3:8698-based imaging. Upon AUY922 treatment, higher radioconjugate uptake was detected in treated MCF-7 xenografts, correlating with an AUY922-induced HER3 upregulation concomitant with an increase in IGF-1Rβ expression.<b>Conclusions:</b> These data underline the potential of HER3-based PET imaging to noninvasively provide information about HER3 expression and to identify patients not responding to targeted therapies due to HER3 recovery. <i>Clin Cancer Res; 24(8); 1853-65. ©2018 AACR</i>.